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Treatment of Metastatic colorectal cancer

Treatment of Metastatic colorectal cancer. Robert Jones Consultant Senior Lecturer Medical Oncology. 71 yo man presents with lethargy, right sided abdominal discomfort and a raised CEA CT CAP shows Liver and Lung metastases and a mass in the region of the sigmoid colon

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Treatment of Metastatic colorectal cancer

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  1. Treatment of Metastatic colorectal cancer Robert Jones Consultant Senior Lecturer Medical Oncology

  2. 71 yo man presents with lethargy, right sided abdominal discomfort and a raised CEA • CT CAP shows Liver and Lung metastases and a mass in the region of the sigmoid colon • What is your management plan?

  3. Establish performance status • Establish nature of sigmoid lesion, flexbile sigmoidoscopy and biopsy • Determine volume of liver and lung disease • Does this patient require removal of the primary before initiating systemic therapy

  4. Which Chemotherapy regimen and when? • Combination regimens associated with greater toxicity (diarrhoea (irinotecan) Neutropenia and neurotoxicity (oxaliplatin) • Does it matter if we treat with different agents in sequence or combination? • Studies addressing this MRC FOCUS and CAIRO

  5. CAIRO study - CKTO 2002-07 R A N D O M I S A T I O N Combination Sequential N = 820 Xeloda XELIRI First-line irinotecan XELOX Second-line XELOX Third-line Koopman et al. Lancet 2007; 370: 135–42

  6. Median overall survival Estimated probability Median OS (months)(95% CI) 1.0 Sequential 16.3 (14.3–18.2) Combination 17.4 (15.2–19.2) 0.8 0.6 p=0.33 0.4 0.2 0.0 0 10 20 30 40 50 Months Koopman et al. Lancet 2007; 370: 135–42

  7. Conclusions – Efficacy • “Combination treatment does not result in an overall survival benefit when compared to sequential treatment in patients with advanced CRC” • “Sequential treatment remains a valid treatment option in this setting” • “Our results may be useful for strategies in which chemotherapy is combined with targeted agents” Koopman et al. Lancet 2007; 370: 135–42

  8. Proportion of patients receiving three drugs in clinical trials is related to OS 22 21 20 19 18 17 16 15 14 13 12 First-line therapy Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5FU2 FOLFOXIRI CAIRO Median OS (months) p=0.0001 0 10 20 30 40 50 60 70 80 Patients with 3 drugs (%) 2007 OS (months) = 13.2 + (3 drugs % x 0.1), R2=0.85 Adapted from Grothey & Sargent. JCO 2005

  9. Caution in these studies • Previously shown patients receiving all 3 drugs do best in metastatic colorectal cancer • Only 19-55% of patients in FOCUS and CAIRO received all 3 • Outcomes in both these trials worse than similar studies • Those patients who did receive all 3 drugs in CAIRO and FOCUS did best • Concern that sequential strategy may reduce proportion of patients receiving all 3

  10. Sequence of combination regimens • Sequence of Folfox vs Folri? • Tournigard JCO 2004 no significant difference • MRC FOCUS, trend in favour of Folfiri • In practice depends on previous therapy • FOLFOXFIRI? vs FOLFIRI; OS of 22.6 mo vs 16.7 mo p=0.033 but with greater toxicity, Falcone JCO 2007

  11. Proposed NICE guidelines 2011 • Recommendations • For patients with advanced and metastatic colorectal cancer, choose one of the following sequences of chemotherapy: • FOLFOX (folinic acid plus fluorouracil plus oxaliplatin) followed by single agent irinotecan or • FOLFOX followed by FOLFIRI (folinic acid plus fluorouracil plus irinotecan) or • XELOX (capecitabine plus oxaliplatin) followed by FOLFIRI. • Decide which combination and sequence of chemotherapy to use after full discussion of the side-effects and the patient‟s preferences.

  12. What about using targetted biological therapies? • Bevacizumab; humanised mAb targeting VEGF-A • Likely acts through several mechanisms • Activity independent of K-RAS status • Cetuximab; targets EGFR • Activity dependent on K-Ras status

  13. Phase III trial of IFL ± bevacizumab: effect of bevacizumab on overall survival 1.0 0.8 0.6 0.4 0.2 0 Kaplan-Meier curve Hazard ratio = 0.66, p=0.00003Median survival15.6 (IFL + placebo)vs 20.3 months(IFL + bevacizumab) Probability of survival IFL + placebo IFL + bevacizumab 0 10 20 30 40 Survival (months) Hurwitz H, et al. NEJM 2004;350(23): 2335-42

  14. NO16966: bevacizumab plus XELOX/FOLFOX4 first-line Significant increase in PFS Bevacizumab + XELOX/FOLFOX4 (n=699) Placebo + XELOX/FOLFOX4 (n=701) 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 HR=0.83p=0.0023 OS estimate PFS estimate HR=0.89 p=0.0769 19.9 21.3 8.0 9.4 0 6 12 18 24 30 36 0 5 10 15 20 25 Time (months) Time (months) Saltz, et al. JCO 2007

  15. E3200: second-line bevacizumab plus FOLFOX4 Significant increase in OS and PFS 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Bevacizumab + FOLFOX 4 (n=280) FOLFOX4 (n=279) HR=0.61p<0.0001 Bevacizumab + FOLFOX4 (n=286) FOLFOX4 (n=291) HR=0.75p=0.0011 OS estimate PFS estimate 4.7 7.3 10.8 12.9 0 10 20 30 40 0 10 20 30 Time (months) Time (months) Giantonio, et al. JCO 2007

  16. CRYSTAL: survival benefit with first-line cetuximab in KRAS wild-type mCRC FOLFIRI (n=350) Cetuximab + FOLFIRI (n=316) 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 HR=0.80p=0.0093 HR=0.70p=0.0012 PFS estimate OS estimate 20.0 23.5 8.4 9.9 0 6 12 18 24 30 36 42 48 54 0 4 8 12 16 20 Time (months) Time (months) Van Cutsem, et al. WCGC 2010

  17. COIN: Cetuximab + CAPOX/mFOLFOX: OS and PFS (KRAS wild-type) OS PFS 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 OxFp OxFp + cetuximab OxFp OxFp + cetuximab HR=0.959(95% CI: 0.84–1.09)p=0.60 HR=1.038(95% CI: 0.90–1.20)p=0.68 PFS estimate OS estimate 17.0 17.9 8.6 8.6 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48 Time (months) Time (months) Maughan, et al. ASCO 2010

  18. PRIME: no OS benefit in KRAS wild-type population FOLFOX4 (n=327) Panitumumab + FOLFOX4 (n=322) HR=0.83; p=0.07 1.0 0.8 0.6 0.4 0.2 0 OS estimate 19.7 23.9 0 6 12 18 24 30 36 Time (months) PRIME: no OS benefit with the addition of panitumumab in KRAS wild-type population Douillard, et al. JCO 2010

  19. VELOUR ESMO 2011/ASCO 2012 • Multicenter, randomized, placebo-controlled Phase III trial involving 1226 patients analysing VEGF trap fusion protein Aflibercept • Patients who failed Oxaliplatin chemotherapy in metastatic setting randomised to FOLFIRI +/- Aflibercept • After a median follow-up of 22.28 months, the Aflibercept group showed superior median overall survival (13.50 months versus 12.06 months, hazards ratio 0.817, P = 0.0032) • No apparent difference according to prior bevacizumab exposure although sub-group analysis did not reach statistical significance

  20. Guidelines for the first-line treatment of mCRC FOLFOX ± bevacizumab NCCN1 XELOX ± bevacizumab Patients appropriatefor intensive therapy FOLFOX ± cetuximab* or panitumumab* FOLFIRI + bevacizumab FOLFIRI ± cetuximab* or panitumumab* 5-FU/LV or capecitabine ± bevacizumab *KRAS wild-type only ESMO2 CT doublet + bevacizumab Wild-type CT doublet + cetuximab Patients appropriatefor intensive therapy KRAS Mutant CT doublet + bevacizumab Unknown CT doublet + bevacizumab 1. Adapted from: NCCN Clinical Practice Guidelines in Oncology: colon cancer. V.3.20112. Adapted from Van Cutsem, et al. Ann Oncol 2010

  21. Patient receives Capecitabine and Oxaliplatin for 3 months • CT shows a partial response • Do you continue with therapy?

  22. Continuous or intermittent? • CR06- No difference in survival between continuous and intermittent with single agent chemo (Maughan et al Lancet 2003) • OPTIMOX2-216 patients- FOLFOX (3/12) followed by 5FU maintenance. Trend to improvement in OS in maintenance arm. (Dictates practice in the US and most of Western Europe) • MRC COIN; 1600 patients- intermittent arm spent 12 weeks less on chemo with a 1.4 month decrease in OS (Maughan et al ASCO 2010)

  23. Case 2 • 67 yo man previously had sigmoid colectomy Dukes C1, completed 6 adjuvant months Folfox 8 months ago, now under surgical follow up • Now presents with right sided abdominal discomfort and rising CEA

  24. What is the next step?

  25. Refer to HPB MDT • Further imaging? • MRI and PET show 5 liver lesions and no other evidence of extra-hepatic disease • How is liver disease defined

  26. Liver metastases in CRC M1a M1b M1c Immediately resectable potentially resectable never resectable Liver MDT agree that all mets can be resected leaving > 30% functional liver All metastases may become resectable if good response to chemotherapy is achieved Metastases so distributed that impossible to achieve resection at any time Liver resection Neoadjuvant CTX New Epoch Pre-operative CTX Palliative CTX FOXFIRE

  27. MDT decides not immediately resectable but potentially resectable • What chemotherapy do you use?

  28. NICE guidance on cetuximab • Aug 2009 based largely on CELIM study Lancet Oncology 2010 • Cetuximab given with 5-fluorouracil, folinic acid and oxaliplatin or irinotecan is recommended as a possible first treatment for people with metastatic colorectal cancer only when: • surgery to remove the cancer in the colon or rectum has been carried out or is possible • the metastases are only in the liver and cannot be removed surgically before treatment • the person is fit enough to have surgery to remove the cancer in the colon or rectum and to have liver surgery if it becomes possible to remove the metastases after cetuximab treatment • the manufacturer refunds 16% of the amount of cetuximab

  29. High response rates in liver-limited disease (data from three randomized trials) 79 CELIM1 FOLFOX/FOLFIRI + ERBITUX LLD KRAS wt1 CRYSTAL2 FOLFIRI + ERBITUX LLD KRAS wt2 77 OPUS3 FOLFOX + ERBITUX KRAS wt3 61 CRYSTAL4 FOLFIRI + ERBITUX KRAS wt4 59 43 43 FOLFIRI wt4 CRYSTAL4 FOLFOX wt3 37 OPUS3 0 10 20 30 40 50 60 70 80 90 Best response rate (%) LLD, liver-limited disease 1. Folprecht G, et al. Ann Oncol 2008;19(Suppl.8):Abstract No. 710; 2. Van Cutsem E, et al. Ann Oncol 2008;19(Suppl. 8):Abstract No. 510PD; 3. Bokemeyer C, et al. J Clin Oncol2009;27:663–671; 4. Van Cutsem et al. N Engl J Med 2009:360:1408–1417

  30. Resection rate is significantly associated with response rate Liver only 0.6 0.5 0.4 All patients 0.3 Resection rate 0.2 0.1 0 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Response rate Folprecht G, et al. Ann Oncol 2005;16:1311–1319

  31. What if MDT decided immediatley resectable? • Role for peri-operative chemotherapy?

  32. Perioperative chemotherapy with FOLFOX4 and surgeryversus surgery alone for resectable liver metastases fromcolorectal cancer; EPOC 364 patients with histologically proven colorectal cancer and up to four liver metastases were randomly assigned to either six cycles of FOLFOX4 before and six cycles after surgery or to surgery alone Overall survival data yet to mature, is chemotherapy delaying or preventing recurrence New EPOC Oxaliplatin or Irinotecan plus 5FU vs Oxaliplatin or Irinotecan plus 5FU plus Cetuximab

  33. New EPOCH Trial design Arm A (control) Chemotherapy 12 weeks Liver resection Chemotherapy 12 weeks Operable (including borderline operable) colorectal liver metastases R Arm B (experimental) Chemotherapy + cetuximab 12 weeks Liver resection Chemotherapy + cetuximab 12 weeks

  34. Primary analysis Chemotherapy Progression free survival of all randomised KRAS wild type patients

  35. Adjuvant chemotherapy after liver resection? • Small number of randomised studies using outdated 5FU/LV regimen; too few patient numbers to show significant advantage. • Meta-analysis and retrospective analyses inidicate advantage for adjuvant chemotherapy. • Trend is now to give FOLFOX based regimens in patients who have undergone primary resection

  36. Option if inoperable but Liver only/predominant • FOXFIRE • Palliative Chemotherapy

  37. Alternative options for inoperable Liver predominant disease • Sirspheres (Foxfire study currently open) • Yttrium 90 loaded microbeads. • Pure β (beta) emitter, average beta energy is 0.9367 MeV • maximum penetration in human tissue of 11 mm, with an estimated effective kill distance in liver tissue and in hepatic tumours of 2.5 mm.

  38. SIR-Spheres microspheres in mCRC Salvage Therapy: Time to Liver Progression in the Belgian Multi-Centre RCT 100 n Median PFS 5FU IV + SIR-Spheres 21 5.5 months P=0.003 5FU IV 23 2.1 months 80 Hazard Ratio 0.38 (95% CI 0.20–0.72) 60 Patients Without Liver Progression (%) 40 20 0 0 2 4 6 8 10 12 26 Time from randomization (months) Hendlisz et al. J Clin Oncol 2010; 28: 3687-3694.

  39. Alternative options for inoperable Liver predominant disease • Sirspheres (Foxfire study currently open) • Radiofrequency ablation • Chemo-embolisation • Microwave ablation

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